The field of the present invention is the area of methods of formulating pharmaceutical compositions for medical and/or veterinary use, in particular, methods of formulating relatively insoluble or toxic materials such as polyene antibiotics, e.g., amphotericin B and nystatin, so that solubility in aqueous milieus is improved and so that toxicity is reduced, release is controlled and in at least some instances, the stability of the formulation is improved. Similarly, solubility is increased and toxicity is decreased for such cancer therapeutic agents as paclitaxel and tamoxifen.
Fungal infections are, in part, associated with immune-compromised patients such as those infected with HIV, patients who have been subjected to anticancer therapeutics or immune suppressive drugs after organ transplants, and the elderly. Fungal infections fall into two categories: systemic (deep) mycoses and superficial mycoses which involve the skin or mucous membranes. The dermatophytic fungi infect the skin, hair and nails; etiological agents include Epidermiphyton spp., Trichophyton spp. and Microspermum spp. Generally, infections of the mucous membranes are due to infections with Candida albicans. The systemic mycoses are serious and often life-threatening. They include cryptococcosis, systemic candidiasis, aspergillosis, blastomycosis, histoplasmosis, coccidiodomycosis, paracoccidioidomycosis, phycomycosis, torulopsosis, among others.
The three families of drugs used to treat fungal infections are the polyenes, imidazoles and antimetabolites. The polyenes include nystatin, which is generally used for superficial infections only, and amphotericin B. Mepartricin and natrimycin are other polyenes with antifungal activities.
Ketoconazole, miconazole and thiabendazole are imidazoles with antifungal activity. They act by inhibiting cytochrome activity and by interfering with ergosterol synthesis. Flucytosine is an antimetabolite which has been used in the treatment of systemic mycoses. It is converted in vivo to 5-fluorouracil, which inhibits thymidylate synthetase.
Amphotericin B (AmB) has an affinity for membranes with a relatively high ergosterol content; it forms channels which allow the passage of potassium and other small molecules. Because the AmB is very toxic, especially in aggregates, and has numerous side effects, it must be given in a hospital setting, adding to treatment costs. There is some evidence (Beringue et al. (1999) J. Gen. Virol. 80, 1873-1877; Beringue et al. (2000) J. Virol 74, 5432-5440) that certain polyenes may inhibit the progression of scrapie infections.
Despite its low solubility in water and the toxicity problems, AmB is one of the drugs of choice for treating fungal infections. Notably, the development of resistance to AmB is very rare. Numerous strategies have been employed to improve its solubility in aqueous systems and to reduce its toxicity. Strategies for the improvement of solubility and toxicity have included formulation with surfactant, e.g. deoxycholate, liposome encapsulation, encapsulation in polyethylene glycol-complexed liposomes and encapsulation with various amphiphilic polymeric materials.
Amphiphilic PEO-block-poly(L-amino acid) (PEO-b-PLAA) polymers may form micelle structures that effectively encapsulate water-insoluble drugs (G. S. Kwon et al. (1994) Colloids & Surfaces B: Biointerfaces 2, 429-434; K. Kataoka et al. (2000) J. Control. Release 64, 143-153;
M. Yokoyama et al. (1998) J. Control. Release 55, 219-229). PEO-b-PLAA micelles are unique among drug carrier systems, owing to nanoscopic dimensions, shell of PEO, and nonpolar core of PLAA, which can take up and “protect” water-insoluble drugs. A primary advantage of PEO-b-PLAA is the potential for encapsulation of drugs by chemical or physical means inside the core of the micelles, consisting of PLAA blocks (M. Yokoyama et al. (1992) Bioconjugate Chem. 3, 295-301; Y. Li and G. S. Kwon (1999) Colloids & Surfaces B: Biointerfaces 16, 217-226; A. Lavasanifar et al. (2000) J. Biomed. Mater. Res. 52 831-835). In either situation, it is possible to tailor the structure of a core-forming PLAA block in order to enhance properties of PEO-b-PLAA micelles for drug delivery (Y. Li, and G. S. Kwon (2000) Pharm. Res. 17(5), 607-611).
Because fungal infections are relatively difficult to treat, because systemic fungal inventions are often life-threatening, and because the antifungal antibiotics are often toxic to animals, including humans, there is a longfelt need in the art for pharmaceutical compositions comprising polyene antibiotics which are improved in relative toxicity to the patient and in release properties. Similarly, there is a need in the art for formulations of certain other pharmaceuticals, including but not limited to taxol, tamoxifen and other anticancer agents.